Our long-term objective is to elucidate how social behaviors, universal features of animals with complex nervous systems, are genetically controlled through the various sensory systems in an organism. As a general strategy, we will utilize Drosophila melanogaster as a model system to elucidate the roles of pheromones and their receptors in social behaviors, such as courtship, mating, aggression etc. In most mammals and insects, the recognition of contact and/or volatile pheromone signals plays a central role in these behaviors. In Drosophila and other insects, members of two families of seven-transmembrane receptors, encoded by the olfactory (Or) and gustatory receptor (Gr) genes, are thought to recognize pheromones. Stimulation of these receptors leads to the activation of neural ensembles in the CNS, which are thought to receive also input from other sensory modalities (i.e. visual and auditory). Finally, a complex neural circuit must integrate the information from these diverse sensory channels and control the elaborate behavioral displays during courtship, aggression and other social interactions between individuals. To understand how such complex, integrated circuits operate is one of the main scientific challenges in modern, molecular neurobiology. We have previously identified a bona fide pheromone receptor, which plays a major role in male courtship. This receptor is encoded by Gr68a, a member of a Gr subfamily, which includes five other Gr genes - Gr32a, Gr39a.a, Gr39a.b, Gr39a.c and Gr39a.d. The central hypothesis of our proposal is that all these Gr genes encode pheromone receptors with specific roles in diverse social behaviors in Drosophila. We shall take a reverse genetic approach to elucidate the roles of these receptors. We will generate knock-out alleles for all six Gr pheromone receptor genes, generate Gr mutant fly strains and perform extensive behavioral analyses with these flies to elucidate Gr gene functions in courtship activation, courtship suppression, aggression, female attraction and other social behaviors. We shall map the axonal projections of Gr-expressing, pheromone-sensing neurons and identify neuronal targets that form synapses with their axons. Finally, we shall identify the main chemical compounds that are recognized by these GR pheromone receptors, and hence, represent the cues that activate these neural circuits. PUBLIC HEALTH RELEVANCE: This grant will investigate the specific role of pheromone receptors in complex social behaviors including sexual behavior, aggression and rejection, using the Drosophila as a model system. The proposed studies will employ extensive genetic analyses, behavioral experiments and neuroanatomical investigations to identify the function of these receptors, with the goal to reveal links between receptors and behavior. Our work will significantly expand our rather poor knowledge of pheromone-guided complex behavior and neural circuits that control them, a hot topic in the field of behavioral and molecular neuroscience.